Accelerated growth of hepatocytes in association with up-regulation of cyclin E in transgenic mice expressing the dominant negative form of retinoic acid receptor

Retinoids play an important role in pathogenesis of liver diseases. To clar ify the functional role of retinoic acid (RA) in liver, we developed transg enic mice (Tg) which express the dominant negative form of retinoic acid re ceptor (RARE) in liver. Here, we report that proliferation of hepatocytes i n RARE Tg is greatly enhanced and that cyclin E is up-regulated in RARE Tg. Liver weight, liver/body weight, and proliferating cell nuclear antigen (P CNA) labeling index in RARE Tg were significantly increased, compared to th ose in wild-type mice (P < 0.01, each). Cell cycle analysis showed that 2N DNA content cells and aneuploid area between 2N and 4N DNA, reflecting S ph ase cells, were significantly increased in RARE Tg, compared to wildtype mi ce (P < 0.01, each). Of G1 phase-related proteins including cyclins, cyclin -dependent protein kinases (CDKs) and cyclin-dependent protein kinase inhib itors (CKIs), cyclin E mRNA and protein was upregulated in liver from RARE Tg by reverse transcription polymerase chain reaction and Western blot anal ysis. Furthermore, the immunoprecipitation with anti-cdk2 antibody, followe d by Western blot analysis with anti-cyclin E antibody indicated that cycli n E/cdk2 complex is increased in liver of RARE Tg. The results of the prese nt study suggest that cyclin E in association with cdk2 governs cell cycle progression through G1 in hepatocytes where function of RA is inhibited. (C ) 2000 Academic Press.